Three murine genes, Dvl-1, Dvl-2 and Dvl-3, are orthologs of dishevelled, a segment polarity gene required for wingless signal transduction in Drosophila. The wnt/wingless signal transduction pathway is conserved from invertebrates to mammals, and plays a crucial role in early embryonic pattern formation. Mutations in murine orthologs of this pathway result in a variety of specific abnormalities to a variety of embryonic and adult tissues, suggesting that the pathway is crucial to mammalian development. We are generating mice homozygous for targeted disruptions of each of the Dvl genes. Mice homozygous for a null allele of Dvl-1 are viable, fertile, and appear grossly normal but are smaller in size than wild type and heterozygous littermates. Dvl-1 -/- mice have significant deficits in memory and learning as determined by acquisition of a passive avoidance task. Motor activity and cerebellar function are unimpaired. Generation of Dvl-2 and Dvl-3 mutant mice are in progress. Dvl-2 chimeras have been produced, which have transmitted the mutant allele to offspring. Dvl-3 targeting constructs have been transfected into embryonic stem cells and are currently being analyzed for correct targeting events.